Process for preparing 2-(4-pyridyl)amino-6-dialkyloxyphenyl-pyrido(2,3-d)pyrimidin-7-ones

ABSTRACT

A one-step process for preparing 2-pyridylamino-pyrido[2,3-d]pyrimidines of Formula II  
                 
 
     wherein Ar is aryl, R′ and R″ are hydrogen, alkyl, halogen, or phenyl, and R 2  is alkyl.

FIELD OF THE INVENTION

[0001] This invention concerns a chemical process for preparingpyrido[2,3-d]pyrimidines having a pyridylamino group at the 2-position.

BACKGROUND OF THE INVENTION

[0002] U.S. Pat. No. 5,733,914 (which is incorporated herein byreference) describes a series of pyrido[2,3-d]pyrimidines that inhibitprotein tyrosine kinase mediated cellular proliferation. The compoundsare anti-angiogenic agents, and as such are useful for treating cancer,particularly leukemia and breast cancer. The U.S. Pat. No. 5,733,914patent teaches that a particularly preferred group of compounds aresubstituted at the 2-position with an arylamino group, and that the arylmoiety can be a pyridyl group.2-(4-Pyridyl)amino-pyrido[2,3-d]pyrimidines appear to be a preferredgroup of compounds because of their metabolic stability and tyrosinekinase selectivity. One such compound, namely2-(pyridin-4-ylamino)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-one,is currently being studied as a possible clinical candidate for treatingcancer.

[0003] According to the synthetic process described in U.S. Pat. No.5,733,914, an alkylsulfanyl (a sulfide) group could not be readilydisplaced by an amine such as a 4-aminopyridine, whereas analkylsulfinyl group (a sulfoxide) could be so displaced. Accordingly,the 2-alkylsulfanyl pyridopyrimidines first had to be oxidized toprovide the corresponding sulfoxide, namely a 2-alkylsulfinylpyridopyrimidine. The use of such oxidants is not only dangerous onlarge scale and often causes over-oxidation, but also is very costly,given that the oxidants are expensive and the process adds anotherchemical step and isolation. This invention avoids these expenses.

[0004] Because these compounds are commercially viable anticanceragents, the need exists for a synthetic process that affords the desiredcompound in high purity and satisfactory yields. This invention providesa commercially viable one-step process for making suchpyridylamino-pyrido[2,3-d]pyrimidines in high yield and high purity.

SUMMARY OF THE INVENTION

[0005] This invention provides a one-step chemical process for preparing2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidines comprising reacting a4-aminopyridine with an alkali metal amide or hydride and a2-alkylsulfanyl-6-aryl-8-substituted-8H-pyrido[2,3-d]pyrimidin-7-one.More particularly, the invention provides a process for reacting a4-aminopyridine of the formula

[0006] with an alkylsulfanyl compound of the Formula I

[0007] in the presence of an alkali metal hydride or amide to provide acompound of Formula II

[0008] wherein:

[0009] “Alkyl” is C₁—C₆ alkyl;

[0010] R′ and R″ independently are hydrogen, C₁—C₆ alkyl, C₁—C₆ alkoxy,halo, hydroxy, phenyl, or C₁—C₆ alkanoyl;

[0011] R² is hydrogen, (CH₂)_(n)Ph, where Ph is phenyl or substitutedphenyl, and n is 0, 1, 2, or 3; heteroaromatic, cycloalkyl, C₁—C₆alkanoyl, C₁—C₆ alkyl, C₂—C₆ alkenyl, and C₂—C₆ alkynyl, where thealkyl, alkenyl, and alkynyl groups may be substituted by NR₅R₆, phenyl,substituted phenyl, thioalkyl, alkoxy, hydroxy, carboxy, halogen,cycloalkyl, and where R₅ and R₆ are independently hydrogen, C₁—C₆ alkyl,C₂—C₆ alkenyl, C₂—C₆ alkynyl, (CH₂)_(n)Ph where Ph is phenyl orsubstituted phenyl, and n is 0, 1, 2, or 3; cycloalkyl, heteroaromatic,and R₅ and R₆ taken together with the nitrogen to which they areattached can complete a ring having 3 to 7 carbon atoms and optionallycontaining 1, 2, or 3 heteroatoms selected from nitrogen, substitutednitrogen, oxygen, and sulfur;

[0012] Ar is phenyl, substituted phenyl, or heteroaromatic;

[0013] and the pharmaceutically acceptable salts thereof.

[0014] Preferably, R′ and R″ independently are hydrogen, C₁—C₆ alkyl,halogen, or phenyl; and

[0015] R² is hydrogen, (CH₂)_(n)Ph, where Ph is phenyl or substitutedphenyl, and n is 0, 1, 2, or 3; heteroaromatic, cycloalkyl, C₁—C₆ alkyl,and C₂—C₆ alkenyl, where the alkyl and alkenyl groups may be substitutedby NR₅R₆, phenyl, substituted phenyl, alkoxy, halogen, cycloalkyl, andwhere R₅ and R₆ are independently hydrogen, C₁—C₆ alkyl, C₂—C₆ alkenyl,(CH₂)_(n)Ph where Ph is phenyl or substituted phenyl, and n is 0, 1, 2,or 3; cycloalkyl, heteroaromatic, and R₅ and R₆ taken together with thenitrogen to which they are attached can complete a ring having 3 to 7carbon atoms and optionally containing 1, 2, or 3 heteroatoms selectedfrom nitrogen, substituted nitrogen, oxygen, and sulfur.

[0016] In a preferred embodiment, R′ and R″ both are hydrogen.

[0017] In another preferred embodiment, Ar is substituted phenyl and ismore preferably 3,5-di-C₁—C₆ alkoxyphenyl. Ar is most preferably3,5-dimethoxyphenyl.

[0018] In another preferred embodiment, R² is C₁—C₆ alkyl.

[0019] Preferably, halogen is bromo, chloro, or iodo.

[0020] In a further embodiment, the alkali metal hydride or amide isselected from the group consisting of lithium hydride, sodium hydride,lithium amide, and sodium amide.

DETAILED DESCRIPTION OF THE INVENTION

[0021] For purposes of the present invention, the terms “alkyl” and“C₁—C₆ alkyl” mean a straight or branched hydrocarbon radical havingfrom 1 to 6 carbon atoms and include, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl,n-hexyl, and the like. The term “C₁—C₆ alkyl” includes within itsdefinition the term “C₁—C₃ alkyl”.

[0022] “Halo” or “halogen” includes fluoro, chloro, bromo, and iodo.

[0023] The terms “alkenyl” and “C₂—C₆ alkenyl” mean a straight orbranched hydrocarbon radical having from 2 to 6 carbon atoms and 1double bond and includes ethenyl, 3-buten-1-yl, 2-ethenylbutyl,3-hexen-1-yl, and the like.

[0024] The terms “alkynyl” and “C₂—C₆ alkynyl” mean a straight orbranched hydrocarbon radical having from 2 to 6 carbon atoms and atleast one triple bond. Typical C₂—C₆ alkynyl groups include propynyl,2-butyn-1-yl, 3-pentyn-1-yl, and the like.

[0025] The terms “cycloalkyl” and “C₃—C₆ cycloalkyl” mean a cyclichydrocarbyl group such as cyclopropyl, cyclobutyl, cyclohexyl, andcyclopentyl.

[0026] The terms “alkoxy” and “C₁—C₆ alkoxy” refer to the alkyl groupsmentioned above binded through oxygen, examples of which includemethoxy, ethoxy, isopropoxy, tert-butoxy, and the like.

[0027] The term “C₁—C₆ alkanoyl” refers to an alkyl group, as definedabove, linked through a carbonyl, i.e., C₁—C₅ alkyl

[0028] Such groups include formyl, acetyl, propionyl, butyryl, andisobutyryl.

[0029] “Acyl” means an alkyl or aryl (Ar) group bonded through acarbonyl group

[0030] For example, acyl includes a C₁—C₆ alkanoyl, includingsubstituted alkanoyl, wherein the alkyl portion can be substituted byNR₅R₆ or a carboxylic or heterocyclic group. Typical acyl groups includeacetyl, benzoyl, and the like.

[0031] The alkyl, alkenyl, alkoxy, and alkynyl groups described abovemay be substituted. The substituent groups which may be part of thealkyl, alkenyl, alkoxy, and alkynyl groups are NR₅R₆, phenyl,substituted phenyl, thio(C₁—C₆)alkyl, C₁—C₆ alkoxy, hydroxy, carboxy,C₁—C₆ alkoxycarbonyl, halo, cycloalkyl, and a 5- or 7-memberedcarbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selectedfrom nitrogen, substituted nitrogen, oxygen, and sulfur. “Substitutednitrogen” means nitrogen bearing C₁—C₆ alkyl or (CH₂)_(n)Ph.

[0032] Examples of substituted alkyl groups thus include 2-aminoethyl,2-diethylaminoethyl, 2-dimethylaminopropyl, ethoxycarbonylmethyl,3-phenylbutyl, methylsulfanylmethyl, methoxymethyl, 3-hydroxypentyl,2-carboxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl, 3-morpholinopropyl,piperazinylmethyl, and 2-(4-methylpiperazinyl)ethyl.

[0033] Examples of substituted alkenyl groups thus include2-diethylaminoethenyl, 3-amino-2-butenyl, 3-(1-piperazinyl)-1-propenyl,3-hydroxy-1-propenyl, 2-(1-s-triazinyl)ethenyl, 3-phenyl-3-pentenyl, andthe like.

[0034] Examples of substituted alkynyl groups include 2-methoxyethynyl,2-ethylsulfanyethynyl, 4-(1-piperazinyl)-3-(butynyl),3-phenyl-5-hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3-butynyl,4-cyclobutyl-4-hexynyl, and the like.

[0035] Typical substituted alkoxy groups include aminomethoxy,trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy,3-hydroxypropoxy, 6-carboxyhexyloxy, and the like.

[0036] Further, examples of substituted alkyl, alkenyl, and alkynylgroups include dimethylaminomethyl, carboxymethyl,4-diethylamino-3-buten-1-yl, 5-ethylmethylamino-3-pentyn-1-yl,4-morpholinobutyl, 4-tetrahydropyridinylbutyl-3-imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-3-yl-butyl, phenylmethyl,3-chlorophenylmethyl, and the like.

[0037] The term “Ar” refers to unsubstituted and substituted aromaticand heteroaromatic groups. Heteroaromatic groups have from 4 to 9 ringatoms, from 1 to 4 of which are selected from O, S, and N. Preferredgroups have 1 or 2 heteroatoms in a 5- or 6-membered aromatic ring. Monoand bicyclic ring systems are included. Typical Ar groups includephenyl, 3,5-dimethoxyphenyl, 3-chlorophenyl, 2,6-dibromophenyl, pyridyl,3-methylpyridyl, benzothienyl, 2,4,6-tribromophenyl,4-ethylbenzothienyl, furanyl, 3,4-diethylfuranyl, naphthyl,4,7-dichloronaphthyl, and the like.

[0038] Preferred Ar groups are phenyl and phenyl substituted by 1, 2, or3 groups independently selected from halo, alkyl alkoxy, thio,thioalkyl, hydroxy, alkanoyl, —CN, —NO₂, —COOR₈, —CF₃, alkanoyloxy, oramino of the formula —NR₅R₆. The alkyl and alkoxy groups can besubstituted as defined above. For example, typical groups arecarboxyalkyl, i.e.,

[0039] alkoxycarbonylalkyl

[0040] hydroxyalkyl and hydroxyalkoxy, (O)₀ or

[0041] and alkoxyalkyl, i.e.,

[0042] Disubstituted phenyl is most preferred, and 2,6-disubstitutedphenyl and 3,5-disubstituted phenyl are especially preferred.

[0043] Typical Ar substituted phenyl groups which are preferred thusinclude 2-aminophenyl, 3-chloro-4-methoxyphenyl, 2,6-dimethylphenyl,2,6-diethylphenyl, 3-hydroxyphenyl, 4-hydroxymethylphenyl,3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,6-dichlorophenyl,4-(3-aminopropoxy)phenyl-, 2-chloro-6-methylphenyl,2,4,6-trichlorophenyl, 2,6-dimethoxyphenyl,4-(diethylaminoethoxy)phenyl, 2,6-dihydroxyphenyl, 2,6-dibromophenyl,2,6-dinitrophenyl, 2,6-di-(trifluoromethyl)phenyl,3-(dimethylaminoethyl)phenyl, 2,6-dimethylphenyl, 2,3,6-trimethylphenyl,2,6-dibromo-4-methylphenyl, and the like.

[0044] The process of this invention is carried out by reacting the2-(alkylsulfanyl)-pyrido[2,3-d]pyrimidine of Formula I, an alkali metalamide or hydride, with a 4-aminopyridine reagent in an organic solventto provide the corresponding2-(pyridin-4-yl-amino)-pyrido[2,3-d]pyrimidine of Formula II. Thereaction occurs as shown below:

[0045] The 4-aminopyridine used in the process has the formula

[0046] wherein R′ and R″ are the same substituents on the pyridyl ringportion of the finished product. The starting pyridopyrimidine ofFormula I and the 4-aminopyridine typically are used in approximatelyequimolar amounts, whereas the alkali metal hydride or amide generallyis used in an excessive amount, for example from about 2 to about 4equivalents relative to the pyridopyrimidine starting material.

[0047] “Base” as used herein means the alkali metal hydride or amide.Typical bases include sodium hydride, sodium amide, lithium hydride, andlithium amide. Also included are potassium amide, potassium hydride,cesium amide and cesium hydride. A preferred alkali metal is lithium anda preferred base is lithium hydride.

[0048] The process of this invention is generally carried out in anunreactive organic solvent. The particular solvent is not critical.Typical solvents commonly used include dimethylsulfoxide,dimethylformamide, acetonitrile, tetrahydrofuran, glyme, diglyme,sulfolane, and N-methylpyrrolidinone (NMP). A nonpolar solvent such astetrahydrofuran is preferred.

[0049] The reaction generally is substantially complete within about 1hour to about 24 hours when carried out at a temperature of about 30° C.to about 120° C. While the exact temperature at which the reaction isconducted is not critical, heating above room temperature is generallypreferred in order to promote substantially complete conversion withinthe above noted time ranges.

[0050] The final product of the process, a2-(pyridin-4-ylamino)-pyridopyrimidine compound of Formula II, isreadily isolated by simply adding water to the reaction mixture toquench the process and to destroy any remaining alkali metal hydride oramide, and then filtering the reaction mixture and, if desired, washingthe precipitate with a solvent such as water or an organic solvent suchas acetonitrile or methanol. The solid product generally is dried in avacuum oven at about 30° C. to about 50° C.

[0051] If desired, the product of Formula II can be further purified byroutine processes such as chromatography, recrystallization fromsolvents such as DMSO, or it can be converted to a pharmaceuticallyacceptable acid addition salt.

[0052] Pharmaceutically acceptable acid addition salts of the compoundof Formula II include salts derived from inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,phosphorous, and the like, as well as the salts derived from organicacids, such as aliphatic mono- and dicarboxylic acids,phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioicacids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Suchsalts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite,nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate,metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate,propionate, caprylate, isobutyrate, oxalate, malonate, succinate,suberate, sebacate, fumarate, maleate, mandelate, benzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate,benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate,maleate, tartrate, methanesulfonate, and the like. Also contemplated aresalts of amino acids such as arginate and the like and gluconate,galacturonate (see, for example, Berge S. M., et al., “PharmaceuticalSalts,” J. of Pharmaceutical Science, 1977;66:1-19).

[0053] The acid addition salts of the basic compounds are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner. The free base formmay be regenerated by contacting the salt form with a base and isolatingthe free base in the conventional manner. The free base forms differfrom their respective salt forms somewhat in certain physical propertiessuch as solubility in polar solvents, but otherwise, the salts areequivalent to their respective free base for purposes of the presentinvention.

[0054] The starting material required for the present process is a2-(alkylsulfanyl)-pyrido[2,3-d]pyrimidine of Formula I. The2-alkylsulfanyl compound is available as described in U.S. Pat. No.5,733,914. For example, an arylacetonitrile is condensed with a2-alkylsulfanyl-4-substituted amino-pyrimidin-5-carboxaldehyde in thepresence of a mild base to give a2-(alkylsulfanyl)-6-aryl-8-substituted-8H-pyrido[2,3-d]pyrimidin-7-imine.The 7-imino group is readily oxidized by reaction with an acid to givethe 2-(alkylsulfanyl)-pyridopyrimidine-7-one of Formula I.

[0055] A preferred method for preparing the 2-(alkylsulfanyl) compoundsof Formula I comprises reacting the 2-(alkylsulfanyl)-4-substitutedamino-pyrimidin-5-carboxaldehyde with an aryl acetic acid ester insteadof an aryl acetonitrile. Use of the aryl acetic acid ester provides thepyridopyrimidine-7-one directly in high yield.

[0056] The present one-step process provides pyridin-4-ylpyridopyrimidines in high yield and excellent purity. The followingdetailed examples further illustrate the process of this invention. Theexamples are provided as illustration only, and are not intended tolimit the invention in any respect.

[0057] 4-Ethylamino-2-Methysulfanyl-Pyrimidine-5-Carboxylic Acid EthylEster

[0058] A 22-L, 4-necked round-bottomed flask was equipped with amechanical stirrer, a dropping funnel, and a thermometer. The flask wascharged with the ethyl 4-chloro-2-(methylthio)-5-pyrimidinecarboxylate(1.53 kg, 6.56 mol), triethylamine (2.74 L, 19.7 mol, 3 eq), and 7.5 Lof tetrahydrofuran to give a solution. The aqueous ethylamine (0.53 L,6.56 mol, 1 eq) was added via the dropping funnel over 20 minutes. Thereaction temperature rose to 35° C. during the addition. The reactionwas stirred at ambient temperature for 2 hours. The reaction was checkedfor completion using TLC (SiO₂; 7:3/heptane:ethyl acetate). Theprecipitate (triethylamine hydrochloride) was filtered off and washed 2times with tetrahydrofuran, combining the washes with the originalfiltrate. The tetrahydrofuran was stripped to near dryness on a rotaryevaporator. The residue was partitioned between saturated aqueous sodiumbicarbonate (500 mL) and ethyl acetate (1 L). Note that there is carbondioxide gas evolution from the bicarbonate both during the partitioningand the subsequent washes. The layers were separated and the organiclayer washed 2 times with saturated aqueous sodium bicarbonate and 1time with brine. The solution was dried over magnesium sulfate,filtered, and stripped to give the titled compound as an off-whitesolid. Yield: 95%.

[0059] 4-Ethylamino-2-Methylsulfanyl-Pyrimidin-5-Yl)-Methanol

[0060] The 50-L built-in reactor was purged with argon 3 times, and thena positive argon pressure was maintained throughout the process. Thereactor was charged with 4 L of tetrahydrofuran, followed by lithiumaluminum hydride (1 M in tetrahydrofuran, 6.77 kg, 7.48 L, 7.48 mol, 1.2eq). The chiller/heater was set to 18° C. and activated. The product ofPreparation 1, 4-ethylamino-2-methylsulfanyl-pyrimidine-5-carboxylicacid ethyl ester (1.5 kg, 6.23 mol, 1 eq), was dissolved in 11 L oftetrahydrofuran (0.58 M) and was added to the reaction vessel using apump over ˜2 hours. TLC (SiO₂; 7:3/heptane:ethyl acetate) was used tomonitor the reaction for completion. When the reaction was complete, thechiller/heater was set to 10° C. The excess hydride was quenched byadding successively: 1.25 L of water, 1.25 L of 15 wt % sodiumhydroxide, and then 4.1 L of water. The first portion of water was addedquite slowly and with vigorous stirring to keep down the foaming and tokeep the temperature below 30° C. As the quench continues, the additionrate was gradually increased until the final portion of water could beadded in a steady stream. The reaction mixture was then stirred for 1hour before filtering through a 1-inch plug of celite in a 2 L coarsefritted funnel. The salts were washed once with tetrahydrofuran on thefunnel. The tetrahydrofuran was stripped, then the residue azeotroped 2times with 1 L portions of toluene. The resulting solid was washed fromthe flask using heptane, then dried in a vacuum oven at 40° C. to givethe titled compound which is used in the next step without furtherpurification.

[0061] 4-Ethylamino-2-Methylsulfanyl-Pyrimidine-5-Carboxaldehyde

[0062] A 50-L round-bottomed flask equipped with a mechanical stirrerwas charged with 565 g (2.84 mol) of the product of Preparation 2,4-ethylamino-2-methylsulfanyl-pyrimidin-5-yl)-methanol, 1.23 kg (14.2mol, 5 eq) of manganese (IV) oxide, and 19 L of chloroform. The mixturewas stirred 24 hours at room temperature, then checked by TLC (SiO₂;7:3/heptane:ethyl acetate) for completion of reaction. The reaction wasfiltered through a plug of celite and the chloroform stripped to givethe titled compound in 90% yield.

EXAMPLE 1

[0063]2-(Methylsulfanyl)-6-(3,5-Dimethoxyphenyl)-8-Ethyl-8H-Pyrido[2,3-d]-Pyrimidine-7-One

[0064] A 5-L round bottomed flask was charged with 516 g (2.62 mol) of4-ethylamino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde, 587 g (2.62mol) of (3,5-dimethoxyphenyl)-acetic acid ethyl ester and 391 mL (2.62mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene. The mixture was heated at80° C. for 1 hour. Thin layer chromatography (TLC) (silica,6:4/heptane:ethyl acetate, developed in an iodine chamber) showed allthe 4-ethylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde wasconsumed. Ethyl alcohol (absolute, 2.75 L) was added to the reactionvessel, which was allowed to cool to room temperature. The solid wascollected by filtration, washed once with ethyl alcohol, and dried in avacuum oven at 45° C. for 12 hours to provide 530 g (57% yield) of2-(methylsulfanyl)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one.Proton NMR (DMSO) is consistent with the structure: ¹H NMR (DMSO): δ8.86(s, 1H), 8.10 (s,1H), 6.83 (d, 2H), 6.51 (s, 1H), 4.36 (q, 2H), 3.75 (s,1H), 2.58 (s, 3H), 1.22 (t, 3H). The combined mother liquor and washeswere allowed to stand at room temperature for 7 days. At this time asecond crop was collected, washed once with ethyl alcohol, and dried ina vacuum oven at 45° C. for 12 hours to provide 79 g (8.5% yield) of2-(methylsulfanyl)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one.Proton NMR (DMSO) is consistent with the structure.

EXAMPLE 1A

[0065]2-(Methylsulfanyl)-6-(3,5-Dimethoxyphenyl)-8-Ethyl-8H-Pyrido[2,3-d]-Pyrimidine-7-One

[0066] 4.8 Kg of4-ethylamino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde and 5.5 Kg of(3,5-dimethoxyphenyl)-acetic acid ethyl ester were dissolved in 10 L ofDMSO at room temperature and stirred. 4.4 Kg of1,8-diazabicyclo[5.4.0]undec-7-ene was added to the reaction mixture.The mixture was heated at about 45-50° C. for at least 3 hours. Thereaction was monitored by reverse-phase HPLC. When the reaction wascompleted, ethyl alcohol (3 L) was added to the reaction vessel, whichwas cooled to 5-15° C. The yellow product was precipitated and collectedby filtration, washed with a mixture of isopropyl alcohol and water (3L+3 L), and dried in a vacuum tray dryer at about 40-45° C. for at least12 hours using a house vacuum (˜30 in Hg) to provide 7.3 Kg (84% yield)of2-(methylsulfanyl)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one.Proton NMR is consistent with the structure.

EXAMPLE 2

[0067]2-(Pyridin-4-Ylamino)-6-(3,5-Dimethoxyphenyl)-8-Ethyl-8H-Pyrido[2,3-d]-Pyrimidin-7-One

[0068] To a 100-mL, three-neck, round bottom flask were added 294.0 mg(3.124 mM) of 4-aminopyridine, 238.8 mg (10.40 mM) of lithium amide, and15 mL of tetrahydrofuran. The reaction mixture was heated to 50° C. for1 hour. A solution of 998 mg (2.792 mM) of2-(methylsulfanyl)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-onein 25 mL of tetrahydrofuran was added in one portion. The reactionmixture was heated at reflux for 24 hours. The reaction mixture wascooled to 50° C. and diluted by dropwise addition of 25 mL of water. Thesolid precipitate was collected by filtration and dried in a vacuum ovenat 45° C. for 12 hours to provide 93.6% yield of the filtered compound,mp 305-307° C. Mass Spec (APCI) 403.9 m/z. HPLC established the productwas 98.5% pure.

EXAMPLE 3

[0069]2-(Pyridin-4-Ylamino)-6-(3,5-Dimethoxyphenyl)-8-Ethyl-8H-Pyrido[2,3-d]-Pyrimidin-7-OneHydrochloride

[0070] To a solution of 88 g (0.93 mol) of 4-aminopyridine in 1 L oftetrahydrofuran was added 21.2 g (2.67 mol) of lithium hydride. Thereaction mixture was heated to 50° C. for 1 hour. To the stirredreaction mixture was added a solution of 318 g (0.89 mol) of2-(methylsulfanyl)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-onein 1.8 L of tetrahydrofuran. The reaction solution was heated at refluxfor 24 hours, and then cooled to 50° C. The reaction mixture was dilutedby the slow addition of a mixture of 500 mL of water and 1 L of 6Nhydrochloric acid. The reaction mixture was cooled to 24° C. and stirredfor 16 hours. The reaction mixture was further diluted by addition of250 mL of acetonitrile and 200 mL of water, and stirring was continuedfor an additional 2 hours. The mixture was then filtered, and the filtercake was dried at 45° C. in vacuo for 12 hours to provide 360 g (92%) of2-(pyridin-4-ylamino)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-onehydrochloride, mp 295-300° C. (dec). HPLC established the purity at 98%.Mass Spec (APCI) 439.89 m/z.

EXAMPLE 4

[0071] Following the general procedure of Examples 2 and 3, 791.0 mg(8.404 mM) of 4-aminopyridine was reacted with 212.5 mg (26.73 mM) oflithium hydride and 3002.4 mg (8.4 mM) of2-(methylsulfanyl)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-oneto give 92.7% yield (95.9% purity) of2-(pyridin-4-ylamino)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-one.

EXAMPLE 5

[0072] By following the general procedure of Examples 2 and 3, 524.2 mg(5.569 mM) of 4-aminopyridine was reacted with 687.4 mg (17.2 mM) ofsodium hydride and 1983.8 mg (5.550 mM) of2-(methylsulfanyl)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-oneto provide 66.3% yield (85.8% purity) of2-(pyridin-4-ylamino)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-one.

What is claimed is:
 1. A process for preparing a2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidine of Formula II

comprising reacting a 4-aminopyridine of the formula

with an alkali metal amide or hydride and a2-alkylsulfanyl-pyrido[2,3-d]pyrimidine of Formula I

wherein: R′ and R″ independently are hydrogen, C₁—C₆ alkyl, halogen, orphenyl; R² is hydrogen, (CH₂)_(n)Ph, where Ph is phenyl or substitutedphenyl, and n is 0, 1, 2, or 3; heteroaromatic, cycloalkyl, C₁—C₆ alkyl,and C₂—C₆ alkenyl, where the alkyl and alkenyl groups may be substitutedby NR₅R₆, phenyl, substituted phenyl, alkoxy, halogen, cycloalkyl, andwhere R₅ and R₆ are independently hydrogen, C₁—C₆ alkyl, C₂—C₆ alkenyl,(CH₂)_(n)Ph where Ph is phenyl or substituted phenyl, and n is 0, 1, 2,or 3; cycloalkyl, heteroaromatic, and R₅ and R₆ taken together with thenitrogen to which they are attached can complete a ring having 3 to 7carbon atoms and optionally containing 1, 2, or 3 heteroatoms selectedfrom nitrogen, substituted nitrogen, oxygen, and sulfur; and Ar isphenyl, substituted phenyl, or heteroaromatic.
 2. A process according toclaim 1 wherein Ar is substituted phenyl.
 3. A process according toclaim 1 wherein Ar is di-C₁—C₆ alkoxy phenyl.
 4. A process according toclaim 1 wherein R² is C₁—C₆ alkyl.
 5. A process according to claim 1wherein R′ and R″ both are hydrogen.
 6. A process for preparing acompound of the formula

comprising reacting 4-aminopyridine with a compound of the formula

in the presence of a base selected from the group consisting of lithiumamide, sodium amide, lithium hydride, and sodium hydride.